Therapeutic effects of
mdmA
(3,4-Methylenedioxymethamphetamine)
Annie Chen
Cynthia Le
Daniel Hagan
Mustafa Nasr
Table of Contents
Mechanism of Action
Therapeutic Neurobiological Mechanism
Neurotoxicity
Long term Serotonergic Changes
Structural Changes in Serotonergic Axons
Role of Oxidative Stress in Neurotoxicity
Safety Assessment in Clinical Studies
Therapeutic Potential
Therapeutic Benefits
Therapeutic Dangers
Mechanism of Action
Primarily serotonergic, but also effects norepinephrine and dopamine
Enters pre-synaptic cell via monoamine transporters
Inhibits vesicular monoamine transporter
Releases monoamines by reversal of respective transporters through
phosphorylation
Also acts as a weak 5-HT, and 5-HT2 agonist
Causes indirect oxytocin secretion by stimulating serotonin system
Inhibits rate-limiting enzyme for 5-HT synthesis; typtophan hydroxylase
MDMA (Ecstasy)
MDMA in synaptic cleft
Therapeutic
Neurobiological
Mechanism
Increased oxytocin levels strengthen alliance
between patients and therapist
Decrease in amygdala activity with an increase in
ventromedial prefrontal activity improves emotional
regulation and decreases fear and avoidance
Increase in norepinephrine and cortisol levels
facilitates emotional engagement and extinction of
learned fear associations
Neurotoxicity
Appears to have same risk for neurotoxicity as other
psycho-stimulants (i.e. methamphetamine)
Very modest risk of acute toxicity in controlled
environment
Studies with animals have shown that MDMA can
decrease brain-functions that rely on serotonin on a
long-term basis ( >7 days)
However, it is unclear what effect this has on the
animals
No studies have investigated whether MDMA causes
neurotoxicity that only becomes apparent with aging
Longterm Serotonergic
Changes
Decreased brain concentrations of serotonin and its
metabolite 5-HIAA
Decrease in density of SERT (serotonin re-uptake
transporter)
Is this down-regulation? Or have serotonergic axons
been permanently lost or damaged?
Down regulation suggests an active adaptation to the
increase in serotonin from ecstasy (MDMA) while
axonal loss suggests true damage
Structural Changes to
Serotonergic Axons
Looking at the structure of serotonergic axons in
animals exposed to MDMA clearly indicates axonal
loss
Slices of MDMA exposed animal brain tissue in
which 5-HT has been stained show irregular swelling
and fragmentation of fine serotonergic axons
Swelling suggest damage of axons and this can be
proven by measuring the movement of compounds
between brain regions connected by serotonergic
axons
Role of Oxidative Stress
in Neurotoxicity
Highly reactive chemicals call free radicals damage
neural molecules through reduction and oxidation.
These reactions alter the ability of neural cells to
carry out their normal functions
MDMA has been shown to increase oxidative stress
in the brain by two separate methods
Antioxidants are molecules that react with freeradicals to create harmless molecules
Role of Oxidative Stress
in
Neurotoxicity
cont...
Mice given extreme doses of antioxidants (or
genetically altered to have naturally elevated levels
of antioxidants) such as vitamin C and alpha-lipoic
acid show no signs of neurotoxicity when given a
normally neurotoxic regiment of MDMA (the dose of
MDMA and vitamin C are very high)
Sustained effects of MDMA may deplete neuronal
energy sources and their ability to deal with oxidative
stress
Both MDMA and Dopamine can be metabolized into
highly reactive molecules
Safety Assessment in
Clinical Studies
Range of psychoactive, but non-neurotoxic MDMA
closes appears small in most animals
However, the dosage and frequency of
administration can be kept to the minimum required
Furthermore, methods for reducing or blocking
neurotoxicity in animals can be employed and likely
reduce neurotoxicity at least to some degree in
humans
Safety Assessment in
Clinical Studies cont...
Methamphetamine has shown to exhibit at least the
same neurotoxicity as MDMA, but the FDA still
approves of methamphetamine
SSRI’s block SERT and inhibits the function of
MDMA
When given 3-4 hours after a neurotoxic regiment of
MDMA, several SSRI’s (such as paroxotine,
fluoxetine and citalopram) can block neurotoxicity in
rodents. Although human-trials have not been
conducted it is likely that they have a similar effect in
humans.
Therapeutic Potential
Physical and Psychological distress of terminal
cancer patients
Treatment of PTSD (post-traumatic stress disorder)
caused by:
Sexual assault
War
Violent crimes
Therapeuti
c Benefits
Helps break down
boundaries in communication
Especially useful for patients
who are aggressive, defensive
and unwilling to “open up”
Increased feelings of
empathy
Increased feelings of
acceptance
Depersonalization; loosening
of ego and boundaries
Therapeutic
Dangers
Chance of psychological
dependence
Possible adverse effects
‣increased body temp
‣increased heart rate and blood
pressure
‣muscle tension
‣jaw clenching nausea
Impairment of episodic and
working memories and attention
History of
Therapeutic Use
of MDMA
Greer & Tolbert
‣MDMA assisted
‣psychotherapy sessions from
‣1980 to 1985
‣80 patients total
‣screening criteria and informed
consent
‣mental set and psychological
preparation emphasized
Role of
Mental Set
Set includes expectations, motivations
and intentions of individual in regard to the
session
Mental set both patient and therapist
important
Goal of developing more compassionate
attitude was easily achieved by MDMAassisted therapy
Relief from chronic symptoms and
behavior problems greater when such
change in attitude occurred
Approached sessions more as sacred
rites of passage than conventional therapy
sessions
Results &
Conclusions
MDMA seems to decrease fear
response to perceived threat to patient’s
emotional integrity
Leads to corrective emotional
experience
Diminishes pathological effects of
previous traumatic experiences
Acquisition of effective skills for
communicating feelings to family
members
Psychological benefits were lasting
up to a 2-year follow-up for most
patients
Therapeutic Use of
MDMA Today
Currently only one FDA & DEA approved medical
study on MDMA (Schedule 1 drug)
MAPS (multidisciplinary association of psychedelic
studies) is studying whether MDMA-assisted
psychotherapy has potential to heal traumas caused
by sexual assault, war, violent crime and other
causes
In the middle of a 10 year, $10 million plan to make
MDMA a government-approved prescription
medication
MDMA-PTSD U.S. Pilot
Study
1st ever protocol evaluating MDMA’s therapeutic
applications in clinical trials
Randomized, double blind and placebo controlled
21 subjects with treatment resistant PTSD
MDMA-assisted psychotherapy produced statistically
significant improvements in PTSD symptoms
Difference between 2 groups was immediate and
maintained throughout the time period
Sources
http://www.maps.org/research/mdma/
http://www.macalester.edu/psychology/whathap/ubnrp/mdma/therapeutic.html
http://www.lycaeum.org/research/researchpdfs/1998_greer_1.pdf
Peroutka, Stephen J. Ecstasy: the Clinical, Pharmacological, and Neurotoxicological
Effects of the Drug MDMA. Boston: Kluwer Academic, 1990.
http://www.science.smith.edu/departments/Biochem/Chm_357/Articles/ecstasy%20toxi
city.pdf
http://www.erowid.org/library/books/ecstasy_complete.shtml
http://www.idmu.co.uk/ecstasy-information/
http://www.springerlink.com/content/9rvc16g5hgmdg6wb/